ZBP1 mediates interferon-induced necroptosis

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Interferons (IFNs) are critical for immune and antiviral responses.
• IFN-induced necroptosis occurs in cells lacking RIPK1, FADD, or caspase-8, but the mechanism remains unclear.

Purpose of the Study:

• To elucidate the mechanism of IFN-induced necroptosis.
• To identify the key molecules involved in IFN-induced necroptosis.

Main Methods:

• Genetic deletion of RIPK1, FADD, or caspase-8 in L929 cells.
• Analysis of IFN-induced necroptosis.
• Identification of ZBP1 as a key mediator.
• Mutation of the caspase-8 cleavage site in RIPK3.
• Assessment of ZBP1 knockout mice in a model of acute systemic inflammatory response syndrome (SIRS).

Main Results:

• ZBP1 (DNA-dependent activator of IFN regulatory factors) is essential for both type I and type II IFN-induced necroptosis.
• L929 cells lacking RIPK1, FADD, or caspase-8 become susceptible to IFN-induced necroptosis.
• ZBP1 is a de novo synthesized protein that triggers necroptosis upon IFN stimulation.
• ZBP1's N-terminal domain mediates homointeraction, and its RHIM domain interacts with RIPK3 to initiate necroptosis.
• Caspase-8 cleavage of RIPK3 is responsible for the antinecroptotic function of RIPK1, FADD, and caspase-8.
• ZBP1 knockout mice are protected from TNF + IFN-γ-induced SIRS.

Conclusions:

• ZBP1 is a critical mediator of IFN-induced necroptosis.
• RIPK1, FADD, and caspase-8 inhibit necroptosis by cleaving RIPK3.
• ZBP1-mediated necroptosis plays a physiological role in inflammatory responses.